Diazines nucleophilic displacements

Formal replacement of a CH unit in pyridine 5.1 by a nitrogen atom leads to the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and pyrazine 10.3. Like pyridine they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. 

The Diazines Pyridazine, Pyrimidine, and Pyrazine Reactions and Synthesis 259 Stannanes can be prepared via nucleophilic displacements at low temperature." ... 

A very characteristic feature of the chemistry of diazines, which is associated with their strongly electron-poor nature, is that they add nucleophilic reagents easily. Without halide to be displaced, such adducts require an oxidation to complete an overall substitution. However, halo-diazines, where the halide is a or 7 to a nitrogen, undergo very easy nucleophilic displacements, the intermediates being particularly well stabilised. 

The MCR mechanism to provide dihydropyridine derivatives starting from enamines is similar to the one discussed for the synthesis of 4//-pyrans 10 (Scheme 13.5) [10]. In contrast to the discussed mechanism, the cychzation in the syntheses of dihydropyridine derivatives takes place by addition/dehydration instead of nucleophilic displacement. As an amidine acts like an enamine as well, the reaction pathway for diazine syntheses can be formulated in analogy to the one discussed for the enamine MCR to create N-substituted 2-amino-4//-pyrans 10 (Scheme 13.5) [11],... 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

The conditions used for nucleophilic attack on pyridine and the diazines are probably too severe and would cause decomposition of the fused systems considered here. Further, the 6-fused pyrazoles would clearly be deactivated to nucleophilic attack and in the c-fused pyrazoles, electron withdrawal by the pyrazole ring would make attack on the six-membered ring difficult. However, displacement of a suitably positioned halide or other good leaving group is often possible. 

Chloro-4-substituted-4/7-benzo-l-thia-2,4-diazine 1,1-dioxides 154 (R = alkyl, Ph R = H, Cl) undergo substitution of the chloride in the presence of amines to provide the 3-(aminoalkyl) derivatives 155 (R = COAr, NH2, NHCOAr) (Equation 26) <2006BMC650>. Compounds related to 154 react similarly with aryl carboxamides in the presence of base to provide the C-3 A-amido analogs of 155 <2006BMC650>. The 3-(bromomethyl)-3,4-dihydro-277-benzo-l-thia-2,4-diazine 1,1-dioxides 156 (R=H, Me, Cl) react with piperidines to afford the substitution products 157 (Equation 27) as do the related 3-(bromomethyl)-277-benzo-l-thia-2,4-diazine 1,1-dioxides <2005BML1185>. Similar displacements with piperazine nucleophiles on N-alkylated 277-thieno[3,4-( ]-l-thia-2,4-diazine-3(477)-one 1,1-dioxides have been reported <2000EJM751>. 

The examples shown below are illustrative of the many easy nucleophilic additions to the polyaza-azines the reaction of 1,2,4,5-tetrazine with simple amines can be contrasted with the requirement for sodamide (Chichibabin reaction) for the diazines and pyridine. The easy addition at C-5 of 1,2,4-tri-azines is shown by the VNS reaction of the 3-methylthio-derivatives in the absence of activating groups the ready displacement of methylthio from the same compound is also indicative. ... 

Displacement of fluoride from furazan 199 is the initial step of a new ring cleavage/ ring closure reactions of tetrazole which provides a route to the new furazano[3,4-e]-l-oxa-3,4-diazine system 200 [99]. Interestingly, the nucleophilic substitution on a second molecule of fluorinated furazan 199 is one of the key steps of the suggested mechanism outlined in Scheme 51. 

The high selectivity in sequential nucleophilic substitution in perfluorodiazines made them attractive scaffolds for the synthesis of a diverse array of polysubstituted diazines. These approaches were recently developed by Stanford group. Thus, tetra-fluoropyritnidine may be used as a scaffold for the synthesis of a range of 2,4,6-trisubstituted pyrimidine derivatives upon sequential displacement of the fluorine atoms attached to the strongly activated 4-, 6- and 2-positions (Table 9) [158]. The first two substitutions proceed in very mild conditioned (0 °C or room temperature). The last nucleophilic substitution of fluorine at 2-position proceeds in harsh conditions and needs MW heating. 

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